Contributions
Abstract: EP1479
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Objectives: To identify the T cell receptor (TCR) characteristics associated with multiple sclerosis (MS) pathogenesis by comparing the TCR repertoire of MS patients and healthy controls (HC).
Methods: Peripheral blood mononuclear cells from 39 MS patients and 19 HC were obtained. There was no significant difference in age at examination, sex, and positivity rate of the susceptibility alleles (HLA-DRB1*04:05 and HLA-DRB1*15:01) in Japanese between the two groups. Next-generation sequencing with an adaptor ligation PCR was conducted for TCR genes (TRA/B/D/G). Diversity index was compared, and the effect of age was examined. Additionally, complementarity determining region 3 (CDR3) sequences of TCR β-chain were extracted and compared between 16 MS patients and 9 HC subjects with HLA-DRB1*04:05.
Results: TCR diversity declined with age in all four TCR genes, especially in the small-expanded clones. In TRA/TRB, diversity index was higher in MS than HC, which was still significant even after correcting for age at examination (p = 0.0043 and 0.024, respectively in Shannon's Index). In HLA-DRB1*04:05-positive individuals, when we focused on the hyper-expanded TRB clones by excluding small-expanded clones to eliminate the effect of age, unique clonotypes exclusively shared by 20% or more of each group was 36 in MS and 106 in HC. By comparing relatedness in all clonotypes, difference was found in amino acids located at the center of the CDR3, which is important for antigen binding, between MS and HC.
Conclusions: In TCR repertoire, small-expanded clones decreased with age and resulted in loss of diversity by aging. There was a difference at the center of the CDR3 between MS and HC with HLA-DRB1*04:05, suggesting a pathogenic role of TCR in MS.
Disclosure: Fumie Hayashi: nothing to disclose.
Noriko Isobe has received grant support from JSPS Kakenhi 18K07529, Japan Intractable Disease research Foundation, Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd., and Japan Blood Products Organization.
Yuri Nakamura has received a grant and salary from Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd., and Japan Blood Products Organization.
Takuya Matsushita has received speaker honoraria payments from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company and Biogen Japan.
Jun-ichi Kira has received grants, consultant fees, speaking fees and/or honoraria from AMED, Health, Labour and Welfare Sciences Research Grants, MEXT KAKENHI, JSPS KAKENHI, Novartis Pharma, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Teijin Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, Astellas Pharma, Pfizer Japan, Eisai.
Abstract: EP1479
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Objectives: To identify the T cell receptor (TCR) characteristics associated with multiple sclerosis (MS) pathogenesis by comparing the TCR repertoire of MS patients and healthy controls (HC).
Methods: Peripheral blood mononuclear cells from 39 MS patients and 19 HC were obtained. There was no significant difference in age at examination, sex, and positivity rate of the susceptibility alleles (HLA-DRB1*04:05 and HLA-DRB1*15:01) in Japanese between the two groups. Next-generation sequencing with an adaptor ligation PCR was conducted for TCR genes (TRA/B/D/G). Diversity index was compared, and the effect of age was examined. Additionally, complementarity determining region 3 (CDR3) sequences of TCR β-chain were extracted and compared between 16 MS patients and 9 HC subjects with HLA-DRB1*04:05.
Results: TCR diversity declined with age in all four TCR genes, especially in the small-expanded clones. In TRA/TRB, diversity index was higher in MS than HC, which was still significant even after correcting for age at examination (p = 0.0043 and 0.024, respectively in Shannon's Index). In HLA-DRB1*04:05-positive individuals, when we focused on the hyper-expanded TRB clones by excluding small-expanded clones to eliminate the effect of age, unique clonotypes exclusively shared by 20% or more of each group was 36 in MS and 106 in HC. By comparing relatedness in all clonotypes, difference was found in amino acids located at the center of the CDR3, which is important for antigen binding, between MS and HC.
Conclusions: In TCR repertoire, small-expanded clones decreased with age and resulted in loss of diversity by aging. There was a difference at the center of the CDR3 between MS and HC with HLA-DRB1*04:05, suggesting a pathogenic role of TCR in MS.
Disclosure: Fumie Hayashi: nothing to disclose.
Noriko Isobe has received grant support from JSPS Kakenhi 18K07529, Japan Intractable Disease research Foundation, Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd., and Japan Blood Products Organization.
Yuri Nakamura has received a grant and salary from Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd., and Japan Blood Products Organization.
Takuya Matsushita has received speaker honoraria payments from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company and Biogen Japan.
Jun-ichi Kira has received grants, consultant fees, speaking fees and/or honoraria from AMED, Health, Labour and Welfare Sciences Research Grants, MEXT KAKENHI, JSPS KAKENHI, Novartis Pharma, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Teijin Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, Astellas Pharma, Pfizer Japan, Eisai.